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Preventive medicine is the rational response to the rising
medical costs. This response includes a renewed emphasis on
antioxidant foods and supplements to lower risk from cancer,
which is now the number one fatal disease. Current theories
of cancer highlight hypoxia in microenvironments where
oxidative stress damages DNA and promotes mutagenesis. Our
major aim is to evaluate suppression of mutagenesis by
sulfhydryl antioxidants N-acetylcysteine (NAC), and alpha-lipoic
acid, both of which potentiate glutathione activity, the
gold standard of antioxidants. Vitamin C will be used as a
standard. Surprisingly, few antioxidant studies have
addressed directly the suppression of mutagenesis. Most rely
on end points of survival times, anticarcinogenic activity,
or chromosomal damage. We hypothesize that the sulfhydryl
antioxidants will prevent mutations induced by hydrogen
peroxide and gamma radiation, treatments that mimic
endogenous mutagenesis by OH radicals. Mutation frequencies
(mf) will be quantitated by measuring mutations in a LacI
repressor gene, contained in the chromosome of live
transgenic Big Blue mice and its cultured cells. Mutations
will be detected because the damaged LacI will not be able
to repress the expression of the reporter gene (b-galactosidase)
in a bacterial system, rendering the resulting plaque blue.
These mf will be compared with those obtained by
quantification of 8-oxo-guanine production. Suppression of
mutations by antioxidants in live Big Blue mice subjected to
gamma radiation will be evaluated by two methods: LacI gene
mutations and 8-oxo-guanine production. This work will test
the notion that antioxidants can effectively block mutations
caused by oxidative damage. In addition, our results will
provide a basis for a rational policy on the use of
antioxidant supplements in humans, either as an anticancer
strategy or for counteracting age-related diseases.
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